1. Field of the Invention
The present invention relates to pharmaceutical compositions and methods for protecting the luminal lining of the gastrointestinal tract from ulceration. In particular, the present invention relates to compositions which include unique mixtures of phospholipids, triglycerides and/or cholesterol which are useful for the treatment or prevention of ulceration of the lining of the gastrointestinal tract.
The present invention also relates to methods and compositions for surfactant replacement therapy and other conditions requiring rapid phospholipid adsorption to surfaces, such as Respiratory Distress Syndrome (RDS).
2. Description of the Related Art
Gastrointestinal ulcer disease, in particular, peptic ulcers, affect 5-15% of the United States population. Moreover, this disease is not restricted to the more industrialized Western culture--indeed, gastric ulceration is even a more serious problem in the Orient. One ulcer disease, particularly worrisome to pediatricians, occurs in premature infants. This condition, known as necrotizing enterocolitis, affects 10-15% of newborns having a birth weight of under 1.5 kg and results in severe ulceration of the small intestine, which frequently requires surgery. The etiology of this condition, like that of peptic ulcer disease, is not understood but it has been postulated that the primary defect lies in an abnormal mucosal defense mechanisms against luminal damaging agents.
Severe ulceration of the gastrointestinal mucosa can also spontaneously occur in the lower bowel (distal ileum and colon) in a spectrum of clinical disorders called inflammatory bowel disease (IFBD). The two major diseases in this classification are Ulcerative Colitis and Crohn's Disease which are associated with severe mucosal ulceration (frequently penetrating the wall of the bowel and forming strictures and fistulas), severe mucosal and submucosal inflammation and edema, and fibrosis. Clinically, patients with fulminant IFBM can be severely ill with massive diarrhea, blood loss, dehydration, weight loss and fever. The prognosis of the disease is not good and frequently requires resection of the diseased tissue. The etiology of IFBD is also poorly understood.
There are many drugs currently on the market to treat peptic ulcer disease. Most of these drugs are directed to neutralizing or inhibiting gastric acid secretion. Notable of the antiulcer compositions are anticholinergics and antihistamines both of which can result in a multitude of undesirable side effects in addition to blocking gastric acid secretion. This form of therapy is based on the tenet "no acid, no ulcer". Although it appears that peptic ulcers will not form in the complete absence of gastric acid, it is generally recognized that not all ulcer patients exhibit enhanced gastric acid output. In fact, gastric ulcer patients as a group have abnormally low gastric acidity. Thus, it has been suggested that gastric acidity may only be an aggravating factor and not a primary cause of gastrointestinal ulcerogenesis.
There is little consensus on the proper medical treatment of necrotizing enterocolitis. Frequently afflicted infants are managed by intravenous hyperalimentation and surgery when life-threatening strictures or perforations result. The medical treatment of inflammatory bowel disease in general is directed to controlling rather than curing the disease. Typical protocols employ steroids and the sulfa drug, Azulfidine (Salicylazosulfapyridine). Although these drugs reduce the mucosal inflammation, diarrhea and even blood loss in chronic inflammatory processes, they have little efficacy in treating the more fulminant forms of the disease. Furthermore, they cause a host of side effects of varying severity in the patients.
An alternative explanation of ulcer incipiency involves the belief that G.I. ulceration develops in individuals that have a defect in a putative "gastrointestinal mucosal barrier." This defect permits luminal damaging agents (acid, enzymes, bile salts, bacteria) to penetrate the surface lining and thereafter promote ulcerogenesis.
It is presently unclear how the normal gastrointestinal (GI) epithelium protects itself from these insults. Indeed, the answer to this fundamental question has long been sought, since it certainly remains a paradox why the stomach does not digest itself while it is constantly bathed in an extremely acidic and proteolytic environment. Conversely, the clinically important question remains as to how and why the element of protection is removed or circumvented in peptic ulcer disease, necrotizing enterocolitis and inflammatory bowel disease. A great deal of research has been performed to answer these important questions. Investigators have postulated that the mucosa is protected by a putative "gastrointestinal mucosal barrier" which prevents the back diffusion of hydrochloric acid and other potentially toxic agents from the lumen into the epithelium. Disruption of this mucosal barrier, results in the development of GI erosions. Although a wide variety of damaging agents such as aspirin, bile salts, hydrochloric acid and alcohol certainly will cause G.I. ulceration if present in high enough concentrations, it is generally believed that the primary cause of ulcer disease in a majority of patients is attributable to a natural defect in the "G.I. mucosal barrier."
Unfortunately, as noted above, most of the existing pharmacological approaches to the treatment of gastrointestinal disease are directed to treating either the gastric acid secretions, for example, through the use of anticholinergics, antihistaminics, and/or antacids, reducing mucosal and submucosal inflammation (steroids) or by physically treating the ulcer itself, for example, with a coating agent such as sucralfate. While the treatment of gastric acid secretion has served to provide some degree of symptomatic and pain relief and occasionally promote ulcer healing, their use is often complicated by undesirable side effects and/or promotion of an acid rebound effect. Sucralfate, on the other hand, is directed to treating the ulcerated tissue directly by forming a physical barrier to gastric contents, and thus does not serve an ulcer preventative function. Moreover, peptic ulcers readily recur at a high rate once patients are withdrawn from therapy with H.sub.2 antagonists or sulcrafate. Similarly the underlying defect in the mucosal barrier which increases a patients susceptibility to inflammatory bowel disease has yet to be identified and it is clear that our present forms of medical therapy for this condition merely treat the symptoms instead of the origin of the disease.
It has been observed by the present inventor that the mucosal surface of certain regions of the gastrointestinal tract have remarkable hydrophobic characteristic that make it non-wettable (i.e.--water-repellant) to the luminal contents. It was of interest that the most hydrophobic gastrointestinal tissues (e.g., the stomach, esophagus and colon) are those regions most susceptible to mucosal ulceration or inflammation. Furthermore, it has been observed that experimental chemicals which induce gastric ulcerogenesis or colitis in laboratory animals result in a marked attenuation of the non-wettable property of the affected mucosal region.
Accordingly, the present invention derives in part from such observations by recognizing a need for a treatment method which is directed to restoring or maintaining the normal hydrophobic character of the luminal lining and thereby prevent or retard the deliterious effects of cytotoxic chemicals in the lumen (e.g., H.sup.+, proteolytic enzymes, endotoxin) to the mucosal lining. Moreover, there is a need for essentially non-toxic agents which may be administered in a convenient dosage form, for example, in a liquid or suspension form, that is well tailored to treat the luminal lining quickly and effectively.
Respiratory Distress Syndrome (RDS) is a debilitating lung disease which is characterized by a decrease in the surface-active material at the air/liquid interface or the pulmonary alveolus. The descriptive term "RDS" has been applied to many acute diffuse infiltrative lung lesions of diverse etiologies when they are accompanied by arterial hypoxemia. Diseases classified generally as Respiratory Distress Syndrome (RDS) range from adult respiratory distress syndromes (ARDS) to a neonatal form, termed variously as idiopathic RDS or hyaline membrane disease. The term RDS is applied to the various forms because of several clinical and pathologic similarities between such acute illnesses in adult and neonatal forms.
Normal lung function depends on the presence of an alveolar lining layer with properties that permit alternate increases and decreases in surface tension, thus, allowing continuous and rapid exchange of O.sub.2 and CO.sub.2 throughout the respiratory cycle. To function properly in the exchange of gases and to maintain its structural integrity, the alveolar lining must retain both its elasticity and stability. The principal mechanism employed by the body to maintain these alveolar properties is through the production of surfactant, primarily by type II alveolar cells. Failure to produce a sufficient amount of surfactant results in both a marked decrease in alveolar elasticity (hence the name, hyaline membrane disease) and alveolar collapse before end-stage expiration resulting in a marked reduction in gas exchange for subsequent respiratory cycles. It is these conditions involving reductions in lung surfactant with which the present invention is also concerned.
Natural lung surfactant is a lipid composition which includes a complex mixture primarily containing phospholipids, certain neutral lipids and proteins, with lipids making up 80% of the composition. The lipid component is composed mainly of dipalmitoyl phosphatidylycholine (dispalmitoyl lecithin), phosphatidyl-glycerol, phosphatidylethanolamine, triglycerides cholesterol and cholesterol esters. The protein components of surfactant required for full surfactant properties include a family of apoproteins. The presence of a number of these apoproteins has been shown to enhance the rate of surface-film formation (See, e.g., Whitsett et al. (1986), Pediatr. Res., 20:460; Avery et al. (1986), New Engl. Jrnl. Med., 315:825).
The treatment of respiratory distress diseases has traditionally been limited to supportive care, including, for example, oxygen administration or even mechanical ventilation. Forced ventilation is not only an inadequate treatment in most severe cases of RDS and surfactant-deficiency RDS, it places mechanical stress on the lungs and diaphragm and can lead to severe alveolar trauma or even pneumothorax.
More recently, progress has been made in the treatment of neonatal and adult Respiratory Distress Syndrome (RDS) by surfactant replacement therapy. (See, e.g., Fujiwara, T., Pulmonary Surfactant (1984); Takahashi, et. al (1986), Biochem. Biophys. Res. Comm., 135:527-532; Metcalfe, et al. (1980), J. Appl. Physiol. 49:34-40.) These surfactant-replacement methods involve the intratracheal instillation of various surfactant mixtures in an attempt to replenish lung surfactant content exogenously. One such surfactant mixture includes dipalmitoyl phosphatidylcholine (DPPC). Corticosteroids have also found some utility in the treatment of RDS, particularly when administered to expectant mothers of premature infants (See, e.g., Ballard et al. (1980), J. Pediatr. 97:451; Papegeorgiou et al. (1981), Pediatrics, 67:416).
Although DPPC is one of the most prominent and surface active of the lipids in pulmonary surfactant, it has been learned that DPPC alone has only marginal therapeutic value. Corticosteroid therapy which has limited effectiveness is also undesirable under certain circumstances due to its multiple systemic actions, for example, as a direct treatment in premature infants or in patients sensitive to corticosteroids.
Although pulmonary installations of mixtures of surface active phospholipids and surfactant-specific apoproteins appear to be an attractive alternative in surfactant replacement therapy (See Hawgood, et al. (1985), Biochem 24:184-190) such a treatment will require significant additional development and expense to identify, purify, clone and/or synthesize the proteins in question before such a treatments therapeutic value may be assessed. Additionally, the possible disadvantage that the surfactant-associated proteins may be immunogenic exits. The use of crude and semipurified bovine pulmonary surfacts in surfactant replacement therapy also presents the disadvantage of being immunogenic, thus inducing an immune reaction in a patient who is already in a debilitated state suffering from RDS. (See Fujiwara, T. Pulmonary Surfactant (1984); Takahashi, et al. (1986) Biochem. Biophys. Res. Comm. 135:527-532).
Unfortunately, present and postulated RDS treatment protocols such as the foregoing fail to provide adequate treatment of all or most cases of RDS. Although purified DPPC has been shown to elicit important surfactant properties in the lungs such as to lower alveolar surface tension and to promote alveolar gas exchange and an increase in the PO.sub.2 content of blood, these effects only occur after an extended amount of time (16-20 hours post-administration). The therapeutic effectiveness of DPPC treatment would therefore be greatly enhanced if a method of accelerating the rate at which DPPC molecules spread over an air/liquid interface while maximally lowering surface tension were developed which did not have the potential complications of systemic side affects or allergic reactions. Such would present an effective surfactant replacement treatment for RDS and other surfactant requiring conditions.